Effect of caffeine consumption on

efficacy of methotrexate in rheumatoid arthritis

01/09/03: Gideon Nesher, MD, Michal Mates, MD and Shoshana Zevin, MD. Shaare-Zedek Medical Center, Jerusalem, Israel

One of the leading theories explaining the mechanism of action of methotrexate (MTX) in rheumatoid arthritis (RA) is indirect inhibition of the enzyme adenosine deaminase, leading to increase in adenosine in the tissues. Adenosine modulates cell functions by interacting with specific receptors on cell membranes, resulting in anti-inflammatory effects.

Caffeine, an ingredient in coffee, tea, cola beverages, cocoa and chocolate, belongs to a family of chemicals called methylxanthines. Methylxanthines interfere with receptors to adenosine. Thus, methylxanthines may interfere with MTX effects. Recently, it has been reported that caffeine reversed the anti-inflammatory effects of MTX in rats with arthritis. As caffeine consumption is very common, we studied whether caffeine intake affected MTX efficacy in patients with Rheumatoid Arthritis.

39 patients with recent-onset Rheumatoid Arthritis were started on MTX (starting dose was 7.5 mg/week). Changes in treatment during the 3 months of follow up were made according to the clinical response of each patient.

Five parameters of disease activity were evaluated prior to commencing MTX therapy and at monthly intervals for 3 months. These parameters were tender joint count, swollen joint count, patients’ assessment of joint pain, duration of morning stiffness and erythrocyte sedimentation rate (ESR). Improvement in each parameter between visits 0 and 3 was calculated. Each patient was instructed to report a daily diet diary on 3 different dates. The amount of caffeine was calculated based on its content in different products. Mean daily intake was than calculated for each case. For evaluation purposes, patients were divided into 3 groups according to the amount of daily caffeine intake: low (<120 mg/day), medium (120-180 mg/day), and high intake (>180mg/day). The mean intake of caffeine for the whole group was 166+82 mg/day, which equals approximately 21/2 cups of instant coffee, 11/4 cups of brewed coffee, 4-5 cans of cola beverages, or 4-5 cups of tea. It should be noted that it is rather difficult to accurately assess the daily caffeine intake. A patient may use different strengths of coffee or tea at different times, or may not drink the whole content of a can or a cup, resulting in overestimation of the actual intake.

Patients with high caffeine intake experienced significantly less improvement in morning stiffness and joint pain, when compared to patients with low caffeine intake. The group of patients with high caffeine consumption improved less in the other parameters (swollen joints and tender joint counts) as well, however these differences did not reach statistical significance.

Based on this observation, it is possible that intake of large amounts of caffeine may interfere with MTX efficacy. In the study showing more significant reversal effect of caffeine on MTX therapy in rats with arthritis, the rats were fed 10 mg/kg/day of caffeine, amount that is 3-5 times higher than consumed by our patients. However, it should be noted that the rat and human caffeine metabolism differ.

Findings in our study are supported by another observation. An abstract in the 2001 meeting of the British Society for Rheumatology, reported on 91 patients treated with MTX: 26% of the patients who discontinued MTX (mostly due to treatment failure) were regular coffee drinkers, compared to only 2% of patients still on MTX (presumably having beneficial response to MTX therapy). It was suggested by the researchers that caffeine interfered with MTX efficacy. However the dosage of MTX was not reported.

The data presented in our study suggest that caffeine, in daily amounts exceeding 180 mg, interferes with MTX efficacy in Rheumatoid Arthritis patients, when compared to patients consuming low amounts (less than 120 mg/day). A larger scale study is needed to further evaluate this possible interaction of caffeine with MTX in Rheumatoid Arthritis patients. In the meantime, it is suggested that patients on MTX therapy limit their caffeine intake, especially in cases where disease activity is not adequately controlled.